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Gene Therapy for Cystic Fibrosis
Overview Cystic fibrosis, also known as mucoviscidosis, is an autosomal recessive genetic disorder. This disease affects cells that produce and secrete mucus, sweat, or digestive liquids. Typically, these fluids act as lubricants and are slippery and thin to allow for proper bodily function; but in patients with cystic fibrosis, these fluids become thick and viscous - sticking to the sides of the affected organs, while clogging tubes, ducts, and various passageways throughout the body. The organs most severely affected by this disorder include the lungs and the pancreas, though the liver and intestine may also be affected. In addition to the accumulation of mucus in the lungs and pancreas, bacterial infections are more common due to the presence of the mucus, which makes it easier for bacteria to grow. Digestive issues are also caused by this disease, as the enzymes secreted by the pancreas to aid in the breakdown of foodstuffs are blocked by the build up of mucus. This causes the incomplete absorbance of nutritional materials from ingested food, as well as bulky stools, intestinal pain and gas, and stomach swelling due to constipation. Patients with this disease also tend to have very salty sweat, which causes them to lose large amounts of electrolytes - this may upset the body's balance and cause a variety of health problems including dehydration, increased heart rate, decreased blood pressure, fatigue, etc. Cystic fibrosis also causes infertility in men and makes it more difficult for women to become pregnant. Occurance & Onset Cystic fibrosis typically occurs in individuals with Northern European ancestry, but may also occur in Hispanics, African' Americans, and some Native Americans. This disease is rarely found in people of Asian and Middle-Eastern ancestry. Prenatal and newborn screening/ genetic testing is performed to check for this disease by testing if the parents possess the CFTR gene mutation. Another method that is sometimes used to tell if a newborn infant has CF is the "sweat test". Symptoms of this disease may not appear in a child afflicted with this disease until their teen or young adult years, and the symptoms of the disease may vary in severity over time. Treatment using gene therapy The cystic fibrosis trans-membrane conductance regulator gene (CFTR) codes for instructions in creating a transport channel for negatively charged chloride ions to move into and out of cells. Mutations in this gene interfere with the function of these channels, causing the control over the movement of water in and out of cells to be disrupted, thus affecting the mucus, digestive fluids, and sweat produced. Gene therapy for this gene began in 1990, with the addition of multiple copies of the normal gene to laboratory cell cultures. In 1993 the first experimental gene therapy treatment was given to a patient using a modified common cold virus to act as the vector in delivering the therapeutic gene to the patient's lung cells. Since then many different delivery methods have been tested in the treatment of this disease including fat capsules (ie. catatonic liposomes), synthetic vectors, nose drops, fluid drips into the lungs, and aerosolized cells via a nebulizer. Currently, there is no gene therapy available for public use. Scientists are still working to determine the best vector and develop the proper DNA cargo to be carried by this vector to have a beneficial effect on the recipients of this treatment. For example: "The CF trial used a liposome delivery method developed at Genzyme awhile ago. But the researchers modified the DNA within to decrease the stretches of cytosine and guanine (“CpG islands”) that invite inflammation and they added a bit to extend the effect. That meant starting from scratch in the phase 1 trial, even though the liposome recipe had been used before." - Ricki Lewis, Ph.D (Source) The number of potential combinations of delivery methods (vectors being just one of them) and modified DNA contents created for each trial is enormous. Though many trials have been conducted within laboratories and a few on people with CF, none have proven to been completely successful in alleviating the patient's symptoms, while doing so in a manner that does not harm the patient in some way (ie. host immune response, inflammatory response, etc.). Not only do these negative responses by the host's cells aggravate the state of the patient, but they also limit the ability of the vectors to persist at the target site, which is critical in properly treating the genetic defect. Potential Risks Due to the use of viral vectors as a delivery method for these potentially therapeutic genes, there are some inherent risks in this mode of gene therapy. These risks include the chance of activating potential oncogenes by accidentally inserting the gene too close to these sequences, a host immune response due to the use of the viral vectors as a delivery method, and inflammatory reactions. References Wiki: Cystic Fibrosis Davies, Jane C., Duncan M. Geddes, and Eric Alton. "Gene Therapy for Cystic Fibrosis." Gene Therapy for Cystic Fibrosis. Wiley Online Library, 06 July 2001. Web. 12 Oct. 2014. . Flotte, Terence, and Beth Laube. "Gene Therapy in Cystic Fibrosis." CHEST Journal | Article. American College of Chest Physicians, Sept. 2001. Web. 12 Oct. 2014. <http://journal.publications.chestnet.org/article.aspx?articleid=1079999>. Mayo Clinic overview of cystic fibrosis NIH Genetic Home Reference: Cystic Fibrosis NIH National Heart, Lung, and Blood Institute overview of Cystic Fibrosis